英国剑桥生物医学园区Philip H. Jones和Benjamin A. Hall研究团队合作取得一项新突破。他们表明空间竞争塑造了正常食管上皮（EE）的动态突变图谱。这一研究成果发表在2020年5月18日的《自然—遗传学》上。

他们研究了诱变处理小鼠的食道上皮中的突变选择问题。深度测序鉴定出了多个带有正向选择的多个基因的突变克隆，包括Notch1，Notch2和Trp53，它们也在人的食道上皮细胞中被选择。转基因谱系追踪揭示了明显的克隆竞争，该竞争随时间而发展。

克隆动力学与简单的模型一致，在该模型中，正向选择的突变所带来的增殖优势取决于邻近细胞的性质。当具有相似竞争适应性的克隆发生碰撞时，突变的细胞命运会朝稳态转变，这是解释选择如何在正常出现的上皮细胞中起作用的一个制约因素。

据悉，在衰老过程中，祖细胞会发生突变，这可能会产生定植到周围组织的克隆。到中年，包括EE在内的正常人类组织已变成由突变克隆拼凑而成。尽管它们与理解衰老和癌症有关，但对正常组织中突变选择的基础过程知之甚少。

附：英文原文

Title: Spatial competition shapes the dynamic mutational landscape of normal esophageal epithelium

Author: Bartomeu Colom, Maria P. Alcolea, Gabriel Piedrafita, Michael W. J. Hall, Agnieszka Wabik, Stefan C. Dentro, Joanna C. Fowler, Albert Herms, Charlotte King, Swee Hoe Ong, Roshan K. Sood, Moritz Gerstung, Inigo Martincorena, Benjamin A. Hall, Philip H. Jones

Issue&Volume: 2020-05-18

Abstract: During aging, progenitor cells acquire mutations, which may generate clones that colonize the surrounding tissue. By middle age, normal human tissues, including the esophageal epithelium (EE), become a patchwork of mutant clones. Despite their relevance for understanding aging and cancer, the processes that underpin mutational selection in normal tissues remain poorly understood. Here, we investigated this issue in the esophageal epithelium of mutagen-treated mice. Deep sequencing identified numerous mutant clones with multiple genes under positive selection, including Notch1, Notch2 and Trp53, which are also selected in human esophageal epithelium. Transgenic lineage tracing revealed strong clonal competition that evolved over time. Clone dynamics were consistent with a simple model in which the proliferative advantage conferred by positively selected mutations depends on the nature of the neighboring cells. When clones with similar competitive fitness collide, mutant cell fate reverts towards homeostasis, a constraint that explains how selection operates in normal-appearing epithelium.

DOI: 10.1038/s41588-020-0624-3

Source: https://www.nature.com/articles/s41588-020-0624-3